Streptococcal cell wall arthritis in LEW/N rats closely resembles rheumatoid arthritis in humans. New data have provided insights into the role of cyclooxygenase in the arthritic process. Moreover, locally produced corticotropin releasing hormone and uteroglobin have also been implicated in the disease process. We have previously presented data indicating that a defective hypothalamic-pituitary-adrenal (HPA) axis response is associated with the extreme susceptibility to arthritis in LEW/N rats and relative resistance in F344/N rats. We have now extended our studies to show that LEW/N and F344/N rats show characteristic behavioral responses consistent with their blunted and robust HPA axis responses, respectively. Ontogenetic studies of the stress response have also shown profound differences between LEW/N and F344/N rats. These observations provide new insights into the role of the stress response and the development of human autoimmune diseases. Acute streptococcal cell wall arthritis severity in LEW/N and F344/N rats is genetically controlled by a limited number of autosomal genes. Genetic linkage studies have been initiated to identify these genes.